The use of engineered biomaterial Bone Plexur M® in benign epiphyseal tumors: our experience at 20 months of follow-up.

The objective is to reconstruct the subchondral bone after curettage of benign tumors located in the epiphysis, a relevant topic in oncological orthopedics. Several bones substituted are commercially available, yet none of these are suitably moldable to repair or be placed in the bone defect; although autologous bone for little defects and homologous for bigger defects are still considered the standard in reconstruction, we verify the ability to adapt and support articular cartilage through the application of Plexur M (Registered Trademark), a newly engineered biomaterial bone. In the present study, we enrolled the first ten consecutive cases referred to our department, where patients were affected by a benign epiphyseal tumor destroying the subchondral bone through to the articular cartilage. Every patient underwent curettage of the disease, apposition of a newly engineered biomaterial bone and filling with homologous morselized bone. The quality of reconstruction was evaluated by two surgeons and by a radiologist based on the achievement of surgical objectives and comparing pre and postoperative imaging. In seven out of eight cases of lesions located in the lower limbs the quality of reconstruction was considered good, restoring an adequate support to the articular cartilage. The quality of the remaining case was considered poor probably due to the extent of the spread of the disease, which destroyed the entire proximal tibial epiphysis. In the two cases where the disease was located in the upper limbs, the Plexur M application restored support to the articular cartilage sufficiently well. However, in the case of a giant cell tumor of the distal radial epiphysis there was a slight reabsorption of the morselized homologous bone. Our series suggest that Plexur M should be considered a valid option for orthopedic surgeons in restoring adequate mechanical support to the articular cartilage; nevertheless, considering its high cost, its use might be reserved to selected cases until further studies can verify the integration process, the effects on the survival of the articular cartilage and on the prevention of premature osteoarthritis.

Radiological evaluation of response in patients with locally advanced/metastatic soft tissue sarcoma treated with trabectedin.

Background: Trabectedin is an antineoplastic drug approved for patients (pts) with advanced soft tissue sarcomas (STS). Interestingly, the radiological evaluation of response during trabectedin therapy is peculiar. Methods: The aim of this single-center retrospective study is to analyze the concordance of response assessment according to RECIST compared with Choi criteria in patients with STS treated with trabectedin between 2009 and 2020 at Regina Elena National Cancer Institute in Rome. Results: We present the preliminary data collected in the last 2 months (mos) on 37 pts who received the diagnosis between 2015 and 2020, with a median age of 52.5 years (range 32-78). The median number of trabectedin cycles administered was four (range 2-50) for a median follow up of 5.83 months (range 1-60). Histological subtypes of STS were five (13.5%) leiomyosarcoma, 14 (37.8%) liposarcoma, nine (24.3%) undifferentiated pleomorphic sarcoma, three (8.1%) synovial sarcoma, and six (16.2%) other rare histological subtypes. Eight pts (21.6%) received trabectedin in the first line setting, 21 (56.8%) in the second line, and seven (18.9%) received it in subsequent lines. One pt received trabectedin as neoadjuvant therapy in a clinical trial (ISG-STS 1001). Median progression-free survival was 3.6 months (CI95% 2.7-4.6); median overall survival was 34.3 months (CI95% 0-75.4). The radiological responses were evaluated with both RECIST and Choi criteria; responses matched in 33 pts (89.2%) but not in four (10.8%). The best responses obtained according to RECIST criteria were two (5.4%) partial response (PR), 13 (35.1%) stable disease (SD), and 22 (59.5%) progressive disease (PD). Instead, two (5.4%), 13 (35.1%), and 22 (59.5%) pts obtained PR, SD, and PD respectively, according to Choi criteria. Cohen's kappa coefficient of concordance was 0.792 (p-value <0.002). A specialized radiologist performed all imaging examinations using a dedicated workstation in the same center. Conclusion: In this first analysis, the concordance between RECIST and Choi assessments demonstrates no statistically significant difference. Responses did not match for four pts. We are expanding the analysis to all pts included in the original cohort to confirm or deny these initial results.

A novel extrusion-based 3D bioprinting system for skeletal muscle tissue engineering.

Three-dimensional (3D) bioprinting is an emerging technology, which turned out to be an optimal tool for tissue engineering approaches. To date, different printing systems have been developed. Among them, the extrusion-based approach demonstrated to be the most suitable for skeletal muscle tissue engineering, due to its ability to produce and deposit printing fibers in a parallel pattern that well mimic the native skeletal muscle tissue architecture. In tissue bioengineering, a key role is played by biomaterials, which must possess the key requisite of 'printability'. Nevertheless, this feature is not often well correlated with cell requirements, such as motives for cellular adhesion and/or absorbability. To overcome this hurdle, several efforts have been made to obtain an effective bioink by combining two different biomaterials in order to reach a good printability besides a suitable biological activity. However, despite being efficient, this strategy reveals several outcomes limitations. We report here the development and characterization of a novel extrusion-based 3D bioprinting system, and its application for correction of volumetric muscle loss (VML) injury in a mouse model. The developed bioprinting system is based on the use of PEG-Fibrinogen, a unique biomaterial with excellent biocompatibility, well-suited for skeletal muscle tissue engineering. With this approach, we obtained highly organized 3D constructs, in which murine muscle progenitors were able to differentiate into muscle fibers arranged in aligned bundles and capable of spontaneously contracting when culturedin vitro. Furthermore, to evaluate the potential of the developed system in future regenerative medicine applications, bioprinted constructs laden with either murine or human muscle progenitors were transplanted to regenerate theTibialis Anteriormuscle of a VML murine model, one month after grafting.

Epithelioid hemangioendothelioma, an ultra-rare cancer: a consensus paper from the community of experts.

Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.

Total serum IgE levels in systemic lupus erythematosus and associations with childhood onset allergies.

Elevated serum IgE has been described in systemic lupus erythematosus (SLE), but associations with disease risk and characteristics remain unresolved. We assessed total serum IgE levels and atopy (IgE > 100 IU/ml) in recently diagnosed SLE patients (n = 228) compared with population controls (n = 293) and in relation to disease activity, autoantibodies, clinical features, total immunoglobulins, C-reactive protein, and allergy history. Multivariate models estimated determinants of IgE and atopy in patients and controls, and associations of SLE with allergy and atopy. Total IgE levels were higher in patients than controls (median = 42 vs. 29 IU/ml); 32% of patients and 25% of controls were atopic (p = 0.06). IgE levels were significantly higher in non-Whites and patients reporting childhood onset (<18 years) asthma and hives, and in controls reporting childhood asthma, hay fever, eczema, and adult onset hives. After accounting for racial differences, atopy was not associated with SLE, nephritis, or other clinical and laboratory parameters. In sum, our findings provide limited evidence of a direct association between total serum IgE and SLE overall or with other disease characteristics after adjusting for demographic characteristics and allergy history. Future studies may want to explore potentially shared risk factors for development of allergy, atopy, and SLE.

The effectiveness of a standard drill connected to a core biopsy needle: How to obtain specimens in very strong bone tumors.

INTRODUCTION: Core biopsy is today recognized as the gold standard for the diagnosis of bone lesions; unfortunately, when the bone is too solid it can be very difficult to penetrate it; in case of failure, open biopsy is indicated but it is associated with greater contamination and complications. A possible solution is to connect a common orthopedic drill to the core biopsy needle. The aim of the presenting study was to present a technique useful for performing biopsies in case of very strong bone lesions and to evaluate the adequacy and quality of the obtained specimen. MATERIALS AND METHODS: A standard bone biopsy set was connected to a commercial drill to perform bone biopsies. Data was collected over a 2-year period (2015-2016). Information regarding technical success, diagnostic data and complication rates was all collated to assess the technical feasibility of this technique. RESULTS: Out of 357 bone biopsies, 34 patients underwent the procedure using a common orthopedic drill connected to a core biopsy needle. Diagnostic material was obtained in each patient and the artifacts were considered irrelevant. No major complications occurred in any patient. DISCUSSION: The use of a core biopsy needle connected to a common orthopedic drill facilitates the penetration of thick cortical bone by simply applying continuous speed and pressure; nevertheless, the biopsy needle we use is not designed for a drilling procedure and for this reason it can be damaged, but if the biopsy is performed with particular attention, the mechanical failure can be avoided CONCLUSIONS: Bone biopsy using a commercial hand drill has a technically high success rate with minimal complications. Further studies with more cases are necessary to verify our results.

Osteoid osteoma treated with radiofrequency ablation in non-operating room anesthesia. A different way of approaching ablative therapy on osteoid osteoma.

OBJECTIVE: The purpose of this study is to verify the effectiveness and complications occurrence of radiofrequency ablation (RFA) in the treatment of osteoid osteoma (OO) in non-operating room anesthesia (N.O.R.A.). PATIENTS AND METHODS: From 2014 to 2017, 61 patients affected by OO (40 men and 21 women) with an age of 20.7 years on average (range, 4-51 years; 12 patients aged 20 years or younger) underwent computed tomography-guided percutaneous radiofrequency ablation (RFA) in N.O.R.A. (Non-Operating Room Anesthesia). Lesion sites treated were: femur (27), tibia (22), pelvis (2), talar bone (3), distal radius (1), and humerus (6). Mean follow-up time was 36 months. In each case, anesthesiologic support followed a new protocol (N.O.R.A. protocol), approved by our Institute. Primary success rate, complications, symptom-free intervals, and follow-up results were evaluated. RESULTS: Pain relief (evaluated with Visual Analogue Scale - VAS) was significant in 97% of patients; it disappeared within 24 hours of the procedure in 44 patients, within 3 days in 10 patients, and within 7 days in 7 patients. After 6 months of observation time, 60 of 61 patients were successfully treated and had no more complaints. In 2 patients, two major complications were found: infection of the site treated, healed with antibiotics, and a nerve lesion, healed with steroid therapy. No other complications were observed. CONCLUSIONS: RFA is a highly effective, efficient, minimally invasive and safe method for the treatment of OO following N.O.R.A.

Mode of action of the bioreductive alkylating agent, 2,3-bis(chloromethyl)-1,4-naphthoquinone.

The bioreductive alkylating agent, 2,3-bis(chloromethyl)-1,4-napthoquinone (CMNQ), has been shown to inhibit the growth of Sarcoma 180 ascites cells in vivo. Evidence for the reductive activation of this agent via the mitochondrial respiratory chain was provided by CMNQ-induced oxidation of reduced nicotinamide adenine dinucleotide; the interaction was shown to be on the substrate side of the site of rotenone inhibition. Consistent with the concept that reduction of CMNQ to a hydroquinone results in the generation of an alkylating species (i.e., a quinone methide) was the finding that radioactivity from [14C]CMNQ present in Sarcoma 180 ascites cells was associated with DNA, RNA, and protein for a period of up to 72 hr after exposure to tumor-bearing animals to this agent. Inhibition of the incorporation of [3H]thymidine, [3H]uridine, and [14C]leucine into DNA, RNA, and protein, respectively, of Sarcoma 180 ascites cells was produced by this agent, with DNA biosynthesis being the most susceptible. The inhibitory effect of CMNQ on the formation of DNA was, at least in part, the result of a prevention of the conversion of thymidine to its nucleotide forms. This action was due to (a) a drug-induced decrease in intracellular levels of adenosine 5'-triphosphate, presumably resulting from uncoupling of oxidative phosphorylation by CMNQ; and (b) a partial loss of thymidine kinase activity in Sarcoma 180 cells, which did not appear to be due to direct inhibition of the enzyme by the drug. Although the primary event produced by CMNQ at the mitochondrial level appeared to be release of respiratory control, other effects of mitochondrial metabolism occurred. These included inhibition of reduced nicotinamide adenine dinucleotide and succinoxidase activities, as previously demonstrated, and mitochondrial swelling, which suggested interaction of CMNQ with the inner mitochondrial membrane. These findings indicate a variety of biochemical lesions are associated with the antineoplastic activity of CMNQ and demonstrate a relationship between the effects of this drug on mitochondrial respiratory control and DNA biosynthesis.

Inhibition of hemoglobin accumulation by monoclonal antibodies to the human transferrin receptor is reversed by hemin.

We have studied the effects of hemin on the inhibition of K562 cell erythroid differentiation mediated by a monoclonal antibody to the human transferrin receptor. In the absence of hemin, the monoclonal antibody 42/6 suppresses the increase of hemoglobin accumulation induced by butyric acid or 5-azacytidine (5-azaCR). In contrast, in the presence of hemin, the hemin-resistant K562(h) cell line is induced to hemoglobin production by treatment with 5-azaCR even in the presence of the monoclonal antibody to human transferrin receptor. The results obtained suggest (1) that the human leukemic K562 cells treated with monoclonal antibodies to human transferrin receptor might retain molecular properties similar to those found in erythroid cells from subjects affected by alterations of iron metabolism, and (2) that hemin might allow hemoglobin synthesis in erythroid cells whose iron uptake is inhibited by monoclonal antibodies to human transferrin receptors.

DNA binding activity and inhibition of DNA-protein interactions. Differential effects of tetra-p-amidino-phenoxyneopentane and its 2'-bromo derivative.

In the present study are reported the differential DNA binding activity of the anti-tumor polyamidine tetra-p-amidinophenoxyneopentane (TAPP-H) and its 2'-halo derivative (TAPP-Br), and their effects on the binding of the recombinant Epstein-Barr virus (EBV) nuclear antigen to a synthetic oligonucleotide mimicking the target DNA sequence present in the EBV genome. In addition, the proliferation kinetics and cell cycle analysis of human leukemia K562 cells treated with TAPP-H and TAPP-Br are reported. The possible in vivo relationship between DNA binding affinity and cytotoxicity is also discussed.

Bioaerosol lung damage in a worker with repeated exposure to fungi in a water-damaged building.

There has been increased concern over health effects related to potential exposure of building occupants to bioaerosols. We report the case of a worker with a respiratory illness related to bioaerosol exposure in a water-damaged building with extensive fungal contamination. We performed environmental tests to evaluate potential exposure to fungi, and we used mycotoxin-specific IgG antibody in serologic studies in the attempt to evaluate exposure to mycotoxins. Extensive fungal contamination was documented in many areas of the building. Penicillium, Aspergillus, and Stachybotrys species were the most predominant fungi found in air sampling. Our serologic test was not useful in differentiating workers who were probably occupationally exposed to mycotoxins from those who were not; however, it did yield evidence that individuals may make specific IgG antibodies to macrocyclic tricothecene mycotoxins. Further research is needed concerning health effects related to bioaerosol exposures, particularly regarding markers of exposure to specific fungi that may produce mycotoxins. In the absence of clinical tools specific for evaluation of mycotoxin-related illness, a systematic clinical approach for evaluating persons with suspected building-related respiratory illness is warranted.